La lecture en ligne est gratuite
Le téléchargement nécessite un accès à la bibliothèque YouScribe
Tout savoir sur nos offres

Partagez cette publication

UNIVERSITEJOSEPHFOURIER
FACULTEDEPHARMACIEDEGRENOBLE


Année:2010



EVALUATIONCLINIQUEPRECOCEENDERMATOLOGIEPARLAMEDECINE
TRANSLATIONNELLE:APPLICATIONPOURUNNOUVELAGENTTOPIQUEDANS
LETRAITEMENTDUPSORIASIS

EARLYSCREENINGINDERMATOLOGYUSINGTRANSLATIONALMEDICINE:
APPLICATIONFORANEWTOPICALAGENTINTHETREATMENTOFPSORIASIS


THESE
PRESENTEEPOURL’OBTENTIONDUTITREDEDOCTEURENPHARMACIE
DIPLÔMED’ETAT

ALINESCHOLLER

Néele:18Octobre1986
A:SaintMartind’Hères

THESESOUTENUEPUBLIQUEMENTALAFACULTEDEPHARMACIEDEGRENOBLE

Le:25novembre2010

DEVANTLEJURYCOMPOSEDE:
Présidentdujury: MrDROUETEMMANUEL
Directeurdethèse: MmeSALINLAURENCE
Membres: MrBAKRIAZIZ
MrSEVEMICHEL

LaFacultédePharmaciedeGrenoblen’entenddonneraucuneapprobationniimprobationauxopinions
émisesdanslesthèses;cesopinionssontconsidéréescommepropresàleursauteur

dumas-00593259, version 1 - 13 May 2011Thèsed’ExercicePharmacie–AlineScholler–Novembre2010
______________________________________________________________________

UNIVERSITEJOSEPHFOURIER
FACULTEDEPHARMACIEDEGRENOBLE
DomainedelaMerci38700LATRONCHE

DoyendelaFaculté:MmeleProfesseurRenéeGRILLOT
Vice-DoyenetDirecteurdesEtudes:MmeEdwigeNICOLLE

Année2009-2010

MAITRESDECONFERENCESDEPHARMACIE(n=32)

ALDEBERT Delphine Parasitologie–Mycologie(L.A.P.M)
ALLENET Benoît PharmacieClinique(ThEMASTIMC-IMAG/MCU-PH)
BATANDIER Cécile NutritionetPhysiologie(L.B.F.A)
BRETON Jean BiologieMoléculaire/Biochimie(L.C.I.B–LAN)
BRIANCON-MARJOLLET Anne PhysiologiePharmacologie(HP2)
BUDAYOVASPANO Monika Biophysique(U.V.H.C.I)
CAVAILLES Pierre BiologieCellulaireetgénétique(L.A.P.M)
CHOISNARD Luc Pharmacotechnie(D.P.M)
DELETRAZ-DELPORTE Martine DroitPharmaceutique
DEMEILLIERS Christine Biochimie(L.B.F.A)
DURMORT-MEUNIER Claire Biotechnologies(I.B.S)
GEZE Annabelle Pharmacotechnie(D.P.M)
GERMI Raphaële Microbiologie(U.V.H.C.I./MCU-PH)
GILLY Catherine ChimieThérapeutique(D.P.M)
GROSSET Catherine ChimieAnalytique(D.P.M)
GUIEU Valérie ChimieAnalytique(D.P.M)
HININGER-FAVIER Isabelle Biochimie(L.B.F.A)
JOYEUX-FAURE Marie Physiologie–Pharmacologie(HP2)
KRIVOBOK Serge BiologieVégétaleetBotanique(L.C.B.M)
MOUHAMADOU Bello Cryptogamie,MycologieGénérale(L.E.C.A)
MORAND Jean-Marc ChimieThérapeutique(D.P.M)
MELODELIMA Christelle ProbabilitésBiostatistiques(L.E.C.A)
NICOLLE Edwige ChimieOrganique(D.P.M)
PEUCHMAUR Marine ChimieOrganique(D.P.M)
PINEL Claudine Parasitologie–MycologieMédicale(CIB/MCU-PH)
RACHIDI Walid Biochimie(L.C.I.B)
RAVEL Anne ChimieAnalytique(D.P.M)
RAVELET Corinne ChimieAnalytiques(D.P.M)
SOUARD Florence Pharmacognosie(D.P.M)
TARBOURIECH Nicolas Biophysique(U.V.H.C.I)
VANHAVERBEKE Cécile ChimieOrganique(D.P.M)
VILLET Annick ChimieAnalytique(VPFormAdjointUJF,D.P.M)

Miseàjourdu03/09/2009
ii
dumas-00593259, version 1 - 13 May 2011Thèsed’ExercicePharmacie–AlineScholler–Novembre2010
______________________________________________________________________

ASSISTANTSHOSPITALO-UNIVERSITAIRES(AHU)(N=2)
BUSSERBenoît Biochimie(IAB,AHU-Biochimie)
MONNERETDenis Biochimie(IAB,AHU-Biochimie)


ENSEIGNANTSANGLAIS(N=3)
COLLEPierreEmmanuel MaîtredeConférence
FITEAndrée ProfesseurCertifié
GOUBIERLaurence ProfesseurCertifié


ATER(N=5)
ATER ELAZZOUZISamira PharmacieGalénique
ATER SHEIKHHASSANAmhed PharmacieGalénique
ATER MASMarie AnglaisMasterISM
ATER ROSSICaroline AnglaisMasterISM
ATER SAPINEmilie PhysiologiePharmacologie


MONITEURSETDOCTORANTScontractuels(N=6)
LydiaCARO(01-10-2007au30-09-2010)
BenjaminDUCAROUGE(01-10-2008au30-09-2011)
RomainHAUTECOEUR(01-10-2008au30-09-2011)
LaurelinePOULAIN(01-10-2009au30-09-2012)
AudreyBOUCHET(01-10-2009au30-09-2012)
MathieuFAVIER(01-10-2009au30-09-2012)

ATER:AttachésTemporairesd’EnseignementetdeRecherches
CHU:CentreHopitaliersUniversitaire
CIB:CentreD’InnovationenBiologie
DPM:DépartementdePharmacochimieMoléculaire
HP2:HypoxiePhysiopathologieRespiratoireetCardiovasculaire
IAB:InstitutAlbertBonniot,CentredeRecherche«OncogenèseetOntogenèse»
IBS:InstitutdeBiologieStructurale
LAPM:LaboratoireAdaptationetPathogénèsedesMicroorganismes
LBFA:LaboratoiredeBioénergétiqueFondamentaleetAppliquée
LCBM:LaboratoireChimieetBiologiedesMétaux
LCIB:LaboratoiredeChimieOrganiqueetBiologie
LECA:Laboratoired’EcologieAlpine
TIMC-IMAG:LaboratoireTechniquedel’Imagerie,delaModélisationetdeCognition
UVHCI:UnitofVirusHostCellInteractions
iii
dumas-00593259, version 1 - 13 May 2011Thèsed’ExercicePharmacie–AlineScholler–Novembre2010
______________________________________________________________________



UNIVERSITEJOSEPHFOURIER
FACULTEDEPHARMACIEDEGRENOBLE
DomainedelaMerci38700LATRONCHE

DoyendelaFaculté:MmeleProfesseurRenéeGRILLOT
Vice-DoyenetDirecteurdesEtudes:MmeEdwigeNICOLLE

Année2009-2010

PROFESSEURSAL’UFRDEPHARMACIE(n=17)


BAKRI Aziz PharmacieGaléniqueetIndustrielle,FormulationetProcédés
Pharmaceutiques(LR)
BOUMENDJEL Ahcène ChimieOrganique(D.P.M)
BURMEISTER Wilhelm Physique(U.V.H.C.I)
CALOP Jean PharmacieClinique(PU-PH)
DANEL Vincent Toxicologie(SMURSAMU/PU-PH)
DECOUT Jean-Luc ChimieInorganique(D.P.M)
DROUET Christian ImmunologieMédicale(GREPI–TIMC)
DROUET Emmanuel Microbiologie(U.V.H.C.I)
FAURE Patrice Biochimie(HP2/PU-PH)
GODIN-RIBUOT Diane Physiologie–Pharmacologie(HP2)
GRILLOT Renée Parasitologie–MycologieMédicale(DirecteurUFR/LAPM,PU-
PH)
LENORMAND JeanLuc IngénieurieCellulaire,Biothérapies(Therex,TIMC)
PEYRIN Eric ChimieAnalytique(D.P.M)
SEVE Michel Biochimie–Biotechnologie(IAB,PU-PH)
RIBUOT Christophe Physiologie–Pharmacologie(HP2)
ROUSSEL Anne-Marie Biochimie-Nutrition(L.B.F.A)
WOUESSIDJEWE Denis Pharmacotechnie(D.P.M)

Miseàjourle03/09/2009









iv
dumas-00593259, version 1 - 13 May 2011Thèsed’ExercicePharmacie–AlineScholler–Novembre2010
______________________________________________________________________


PROFESSEUREMERITE(N=1)
FAVIER Alain


PROFESSEURSASSOCIES(PAST)(N=3)
BELLET Béatrice PharmacieClinique
RIEU Isabelle Qualitologie(PraticienAttaché–CHU)
TROUILLER Patrice SantéPublique(PraticienHospitalier–CHU)



PROFESSEURAGREGE(PRAG)(N=1)
GAUCHARD PierreAlexis Chimie(D.P.M)



CHU:CentreHopitaliersUniversitaire
DPM:DépartementdePharmacochimieMoléculaire
HP2:HypoxiePhysiopathologieRespiratoireetCardiovasculaire
IAB:InstitutdeBiologieStructurale
LBFA:LaboratoiredeBioénergétiqueFondamentaleetAppliquée
LCIB:LaboratoiredeChimieOrganiqueetBiologie
LR:LaboratoiredesRadioPharmaceutiques
PAST:ProfesseurAssociéàTempsPartiel
PRAG:ProfesseurAgrégé
UVHCI:UnitofVirusHostCellInteractions


v
dumas-00593259, version 1 - 13 May 2011Thèsed’ExercicePharmacie–AlineScholler–Novembre2010
______________________________________________________________________

-ACKNOWLEDGEMENTS-
ItisarealpleasureformetoattendthisthesisinfrontofEmmanuelDrouet,
AzizBakriandMichelSèvewhosharedtheirpassion,believedinmeandwhomademe
lovewhatIdo.
IamgratefultomyCompanysupervisor,LaurenceSalin,whogavemethe
opportunitytodomyplacementinGaldermaandwhoseencouragement,guidance
andsupporthelpedmeinthecompletionofmythesis.
IwanttogiveaspecialthankstoAnnickJaninwhoofferedmeinvaluable
assistancebysharingherknowledgeandexperience.
It is a pleasure to thank Philippe Andres, the head of the Early Clinical
Evaluationdepartment,forhisprecioustimeandwiseadvice.
I am indebted to many of my colleagues (Khaled Benkali, Andre Jomard,
NathalieKucharczyk,AnneLeFlamanc,AnnePascaleLuzyandIrinaSafonova),fortheir
time and kindness, and for providing me with precious comments on my thesis,
accordingtotheirexpertise.
Ioffermyregardstoallofthosewhosupportedmeinanyrespectduringthe
completionoftheproject.
Lastly, I would like to thank all my friends who came to see me during
weekendsandencouragedmeinmywork.Iwouldliketoshowmygratitudetomy
belovedfamilyandtoMatthieuMoureywhoalwaysunderstoodmeandhavebeen
hereforme.
vi
dumas-00593259, version 1 - 13 May 2011Thèsed’ExercicePharmacie–AlineScholler–Novembre2010
______________________________________________________________________

-FOREWORD-
ThisThesiswaselaboratedduringmyMaster2placementperiodspentinthe
EarlyClinicalEvaluation(ECE)departmentoftheworldfirstdermatologicalcompany
calledGalderma.
Createdin1981,thispharmaceuticalcompanyisajointventurebetweenNestlé
andl’Oréalemployingmorethan3000collaboratorsin31subsidiariesworldwide.
UnderthedirectionofHumbertoC.Antunes(CEO),thecompanyrepresents7.2%of
the worldwide dermatological market share in 2009. 20.8% of its turnover (978
Millions)isdedicatedtoinnovationanddevelopmentofdrugsandmedicalsolutions,
issuedfromresearch.GaldermaR&DactivitiesarebasedinSophiaAntipolis(France),
Princeton (USA) and Tokyo (Japan). Committed to the future of dermatology,
Galdermafocusesonpathologiessuchasacne,psoriasis,rosacea,atopicdermatitis,
pigmentationdisorders,skinaging,skincancerandonychomycosis.

The choice of this thesis was considered according to the thoughts and
activities performed during my placement within the early clinical evaluation
department.ThetitleoftheThesisisthefollowing:‘Earlyscreeningindermatology
usingtranslationalmedicine:Applicationforanewtopicalagentinthetreatmentof
psoriasis’whichis,inmyopinion,agoodsummaryoftheECEobjectivesandactivities
inwhichIparticipatedinthiscompany.
Beforereachingthisthought,Ihadtounderstandthecompanystrategyin
termsofresearchanddevelopmentobjectives.Ihavemetalargenumberofpeoplein
early development such as managers of the early clinical department, advanced
pharmacology, early ADMET, early formulation, toxicology, etc… These meetings
helpedmeappreciatetheirmission,theirresearchstrategy,aswellastheiractions
andobjectivesfacingconcernsofthecurrentapproachinearlydrugdevelopment,
especiallyinthetreatmentofpsoriasis.Indeed,thereisastrongwilltointegrate
translationalmedicineattheinterfacebetweenResearchandDevelopment.

Myinvolvementinscientificdocumentationwriting,setting-up,follow-upand
dataanalysesofseveralclinicalstudieshelpedmeappreciatetherationalandthe
developmentstrategyinvolvedinclinicalprojects.Inaddition,workingalongside
clinicalscientists,researchersandclinicaltrialadministratorsmademefamiliarisewith
jobs in clinical research as well as the required skills. Besides, interactions with
researchers,statisticians,datamanager,qualityinsurance,pharmacovigilance(etc…)
showedmehowimportantitistoworkinmultidisciplinaryteams.
vii
dumas-00593259, version 1 - 13 May 2011Thèsed’ExercicePharmacie–AlineScholler–Novembre2010
______________________________________________________________________

TableofContents
-ACKNOWLEDGEMENTS-.....................................................................................................VI
-FOREWORD-.....................................................VII
-LISTOFFIGURES–...............XI
-LISTOFABBREVIATION-....XIII
-INTRODUCTION(FRANÇAIS)-...............................................................................................XIV
-RESUMEDELATHESE(FRANÇAIS)-.......................XV
CHAPTER1:BACKGROUNDANDLITERATUREREVIEW–........................................................1
INTRODUCTION.............................................................................................1
1.1 CURRENTCHALLENGESFACEDBYPHARMACEUTICALINDUSTRY.........................4
1.1.1 PHARMACEUTICALCOMPANIESAREFACINGARESEARCH&DEVELOPMENTPRODUCTIVITYGAP..........4
1.1.1.1 DRUGDISCOVERY,DEVELOPMENTANDAPPROVALPROCESS.......................................................4
1.1.1.2 RESEARCH&DEVELOPMENTEXPENDITUREVERSUSNEWMOLECULARENTITIESOUTPUT.................4
1.1.1.3 ATTRITIONRATE................................................................6
1.1.1.4 REASONSFORDEVELOPMENTFAILURES..................8
1.1.2 CHANGINGDEVELOPMENTPARADIGM......................................................9
1.1.2.1 LEARN-AND-CONFIRMPARADIGMPROPOSEDBYSHEINER.........................9
1.1.2.2 THEFDA’SCRITICALPATHCHALLENGE.................................................10
1.1.2.3 CRITICALPATHINITIATIVE..................................................................12
1.2 RATIONALEANDCHALLENGESINDRUGDISCOVERYANDDEVELOPMENTINPSORIASIS.........................14
1.2.1 GENERALITIESONPSORIASIS.................................14
1.2.1.1 EPIDEMIOLOGIC&CLINICALFEATURES.................................................................................14
1.2.1.2 AETIOLOGYANDPATHOPHYSIOLOGY...................16
1.2.2 MANAGEMENTOFPSORIASISDISEASE:AFOCUSONTOPICALTHERAPIES.......18
1.2.2.1 PRESENTSTATEOFMARKETEDTOPICALTHERAPIESINPSORIASIS...............18
1.2.2.2 CONSENSUS,GUIDELINES,ANDEVIDENCE-BASEDDERMATOLOGY:.............................................21
1.2.2.3 NEWDIRECTIONSFORFUTURETOPICALTHERAPYOFPSORIASIS................21
1.3 LIMITATIONSANDPERSPECTIVESINDEVELOPINGNEWTOPICALTHERAPIESFORPSORIASIS...................24
1.3.1 PARTICULARITIESANDCONCERNSREGARDINGTHEROUTEOFADMINISTRATION.............................24
1.3.1.1 TYPEOFMOLECULE-SKINBARRIER&TOPICALDELIVERY........................................................25
1.3.1.2 PERCUTANEOUSABSORPTION&FORMULATIONASPECTS27
1.3.1.3 TOPICALAPPLICATIONONTHESKIN.....................................................28
1.3.1.4 SAMPLINGMETHODS........................................................................29
1.3.1.5 REGULATORYGUIDELINES..................................29
1.3.1.6 TOPICALDRUGDEVELOPMENTTIME....................29
1.3.2 LIMITATIONSOFCURRENTNON-CLINICALMODELSINPSORIASISRESEARCH....30
1.3.2.1 PHARMACOLOGICALMODELSOFPSORIASIS&PERSPECTIVES...................................................31
1.3.2.2 DERMALPHARMACOKINETICSMODELS&PROSPECTS.............................35
1.3.2.3 SAFEFIRST-IN-MANSTARTINGDOSE&SYSTEMICTOXICITY&LOCALTOLERANCE........................38
1.4 EARLYCLINICALTRIALSINPSORIASIS..........................................................................................39
1.4.1 STREAMLININGOFCLINICALRESEARCH....................39
1.4.2 INNOVATIONINCLINICALTRIALDESIGNS&NOVELSCREENINGMETHODOLOGIESINPSORIASIS..........40
1.4.2.1 INNOVATIONINCLINICALTRIALSTRATEGIES................................................................41
1.4.2.2 INNOVATIVECLINICALTRIALDESIGNSINDERMATOLOGYANDPARTICULARLYINPSORIASIS.............43
1.4.2.3 NEWTOOLSTOASSESSHUMANPKAND/ORPDSKINPARAMETERS..........46
viii
dumas-00593259, version 1 - 13 May 2011Thèsed’ExercicePharmacie–AlineScholler–Novembre2010
______________________________________________________________________

CHAPTER2:AIMS&OBJECTIVES–.......................................................................................52
2.1 HYPOTHESIS..........................................................52
2.2 AIMS....................................53
2.3 OBJECTIVES...........................54
CHAPTER3:MATERIALS&METHODS–...............................................................................56
3.1 MATERIALS&METHODSUSEDFORTHELITERATUREREVIEW.........................56
3.2 MATERIALS&METHODSUSEDFORTHEEARLYCLINICALSTUDIESOFINTEREST..................................57
3.2.1 21-DAYTOLERANCEPHASELHUMANPHARMACOLOGYINHEALTHYVOLUNTEERS..........................58
3.2.2 POCPHASEIHUMANPHARMACOLOGYINPSORIATICPATIENTS...................................................60
3.2.3 EVALUATIONTOOLSUSEDFORDERMALMEASUREMENTS...........................63
3.3 MATERIALS&METHODSOFTHENON-CLINICALSTUDYOFINTEREST................64
3.4 STATISTICALANALYSISOFTHESKINDISTRIBUTIONRESULTS............................................................65
CHAPTER4:RESULTS–........................................................................................................66
4.1 SUMMARYOFTHESKINDISTRIBUTIONRESULTSINHEALTHYVOLUNTEERS.........66
4.1.1 INTRODUCTION...................66
4.1.2 KEYRESULTS.......................................................................................................................66
4.1.3 DETAILEDRESULTS...............................................................................67
4.1.3.1 DRUGACUMULATEDCONCENTRATIONINTHESC,THE(E+D)ANDINTHETOTALSKIN(SC+E+D):67
4.1.3.2 DRUGACONCENTRATIONPROFILETODETERMINEDRUGDISTRIBUTIONINTHESC......................68
4.2 SUMMARYOFTHESKINDISTRIBUTIONRESULTSINPSORIATICPATIENTS............69
4.2.1 INTRODUCTION...................................................................................................................69
4.2.2 KEYRESULTS......................69
4.2.3 DETAILEDRESULTS..............70
4.2.3.1 DRUGACUMULATEDCONCENTRATIONINTHESC,THE(E+D)ANDTHETOTALSKIN(SC+E+D):...70
4.1.3.2 DRUGACONCENTRATIONPROFILETODETERMINEDRUGDISTRIBUTIONINTHESC......................72
4.3 SUMMARYRESULTSOFIN-VITROLIBERATIONPENETRATIONSTUDY.................................................73
CHAPTER5:DISCUSSION–...................................................................76
5.1 INTRODUCTION......................................................76
5.2 CLINICALSKINDISTRIBUTIONDATACROSSANALYSIS:NORMALSKIN(HEALTHYVOLUNTEERS)VERSUS
PSORIATICSKIN(PATIENTS)................................................................................78
5.2.1 DATACOMPARISON.............................................78
5.2.2 DOESPSORIATICSKIN(I.E.PATHOLOGICALSKIN)IMPACTSDRUGAPENETRATION?COULDHEALTHY
VOLUNTEERSBEPHARMACOLOGICALMODELSFORPSORIATICPATIENTS?...................81
5.2.3 LIMITSINTHEINTERPRETATION.............................................................................................82
5.2.4 WERETHEREANYRELATIONSBETWEENSKINDISTRIBUTIONRESULTSSAFETYANDEFFICACYOBJECTIVES
OFTHESTUDYPERFORMEDINPSORIATICPATIENTS................83
5.3. OVERALLCROSSANALYSIS.......................................................................................................85
5.3.1 DATACOMPARISON.............85
5.3.2 DOESLIBERATION-PENETRATIONSTUDYREFLECTCLINICALSITUATIONSINHEALTHYVOLUNTEERSAND
PSORIATICPATIENTSTREATEDWITHDRUGA?......................................................................................88
CONCLUSION-.....................................................92
-CONCLUSION(FRANÇAIS)-...................................................................................................95
-REFERENCES-.....................98
ix
dumas-00593259, version 1 - 13 May 2011Thèsed’ExercicePharmacie–AlineScholler–Novembre2010
______________________________________________________________________

-APPENDICES-...................................................................................................................103
-SERMENTDESAPOTHICAIRES-.........................106
-ABSTRACT-......................107

x
dumas-00593259, version 1 - 13 May 2011